A common variant (rs738409 C>G) in the PNPLA3 gene has been consistently associated with liver fat but also fibrosis in nonalcoholic fatty liver disease, alcoholic liver disease (ALD), and chronic hepatitis C (CHC).1-4 The study by Valenti et al.4 in a recent issue of HEPATOLOGY shows that in Caucasian CHC patients, this variant was also linked to hepatocellular carcinoma (HCC). This latter finding has been replicated in another independent European cohort.5
We tested the association between rs738409 and HCC in ALD. To this end, we genotyped 325 Caucasian patients from Belgium with alcoholic cirrhosis (67% men; mean age, 54.9 ± 9.1 years; mean body mass index [BMI], 26.7±5.5 kg/m2; 17% had diabetes) and 246 French Caucasian patients with alcoholic cirrhosis (86% men; mean age, 64.3±9.1 years; mean BMI, 27.4±4.9 kg/m2; 37% had diabetes). HCC was confirmed by histology or typical imaging findings in 12% of the Belgian cohort and 43% of the French cohort. The French unit included a higher proportion of HCC patients, reflecting the specificity of this tertiary center specializing in liver cancer management. HCC was present in 9% of CC, 10% of CG, and 25% of GG genotype in the Belgian cohort and in 28% of CC, 41% of CG, and 78% of GG genotype in the French group. The minor allele frequency was not statistically different between the Belgian and French centers (36.8% versus 39.8% [P = 0.296]). Under a recessive model of inheritance, rs738409 was significantly associated with HCC after adjustment for, age, sex, BMI, and diabetes in both cohorts (Table 1).
|Belgian Cohort (n = 325)||French Cohort (n = 246)||Overall (n = 571)|
|OR (95% CI)||P||OR (95% CI)||P||OR (95% CI)||P|
|rs738409 GG*||3.17 (1.39-7.21)||0.006||9.23 (3.37-25.27)||1.50 × 10−5||4.70 (2.63-8.42)||1.83 × 10−7|
|Age, years||1.04 (0.99-1.08)||0.107||1.09 (1.05-1.13)||2.00 × 10−5||1.08 (1.06-1.11)||5.36 × 10−10|
|Sex, men||1.15 (0.53-2.51)||0.728||14.03 (2.94-66.90)||0.001||3.17 (1.64-6.13)||0.001|
|BMI (kg/m2)||1.05 (0.98-1.12)||0.150||1.03 (0.97-1.11)||0.349||1.04 (0.99-1.08)||0.146|
|Diabetes||2.30 (1.05-5.04)||0.038||1.39 (0.73-2.65)||0.322||1.89 (1.17-3.04)||0.009|
The rs738409 variant is associated with liver fat accumulation; however, the exact function of PNPLA3 and the consequence of the related nonsynonymous variation remains unknown.6 Although the remarkable observation that rs738409 confers higher risk of HCC in CHC and ALD warrants additional replication, it may well illustrate gene-host interactions and indicate that the influence of PNPLA3 on chronic liver disease heritability could go far beyond a mere impact on steatosis.